DESCRIPTION (Applicant's abstract): Previous studies from our laboratory and others have demonstrated that the cerebellum, particularly the rostral fastigial nucleus (FNR), plays a facilitatory role in the respiratory response to stress, especially to severe hypercapnia. To date, the mechanisms underlying cerebellar involvement in the respiratory response to hypercapnia remain unknown. Recent evidence utilizing both in vivo and in vitro (cell culture) techniques raises the possibility that some FNR neurons may be chemosensitive. Therefore, we hypothesize that the ability of the cerebellum to modulate the ventilatory response to acidic stimulation (CO2/H+) is, at least partially, attributed to activation of FNR chemosensitive neurons. Furthermore, we will investigate synaptic projections and neurotransmitters utilized by these chemosensitive neurons to modulate the respiratory response. Specific aims are to: 1) determine the unique involvement of the FNR neurons in the respiratory response to hypercapnia as compared to other deep cerebellar nuclei; 2) verify the presence, location and electrophysiological characteristics of chemosensitive neurons within the FNR responsible for respiratory augmentation to focal tissue acidification; 3) identify the synaptic connections of the FNR neurons essential to this FNR-mediated respiratory response; and 4) demonstrate the involvement of glutamate and/or gamma-aminobutyrate (GABA) as potential neurotransmitters in this FNR efferent pathway. This proposal will elucidate how the cerebellum facilitates the respiratory response to CO2/H+ stimulation by using multi-disciplinary approaches (electrophysiology, immunohistochemistry and pharmacology). The results will substantially broaden our general knowledge of the central network involved in chemical control of breathing and enhance our understanding of the neurochemical mechanisms underlying centrally mediated respiratory responses to physiological stress, such as exercise. Perhaps, more exciting is the emerging concept that the cerebellum may be far more involved in the planning and executing of motor responses, including respiration, than we have heretofore imagined.